The circadian clock controls a remarkable array of physiological and metabolic functions. This regulation is achieved through a network of transcriptional-translational loops operated by a complex molecular machinery. We have been interested in dissecting the molecular gears of the circadian clock, a regulatory system that governs a significant fraction of the genome (10-20% of the genes). Our recent research has revealed unexpected links between circadian regulators, chromatin remodeling and cellular metabolism. Complex programs of gene expression characterize circadian rhythms that represent a paradigm for dynamic changes in chromatin transitions. Accumulating evidence has implicated the histone deacetylase SIRT1 in circadian regulation, a key discovery since this enzyme utilizes NAD+ as coenzyme, thereby linking energy metabolism to circadian regulation. Recent results in our laboratory however indicate that SIRT1 can't be the whole story: other sirtuins operate in the nucleus and one of them, SIRT6, is tightly associated to chromatin and has been shown to play a critical role in cellular metabolism. Our preliminary data clearly show that SIRT6 plays a critical role in circadian regulation, suggesting the fascinating possibility tht SIRT1 and SIRT6 may functionally interplay in the control a circadian gene expression and histone acetylation. These results reveal a novel function of SIRT6, a novel pathway of circadian control and the first example of interplay between sirtuins. The aims of the proposal are thereby to fully elucidate how and when SIRT6 operates in the circadian cycle. To do so, we will employ a number of molecular, genetic and physiological approaches. The final goal of this proposal is to obtain an intimate understanding of the molecular mechanisms through which chromatin remodeling and metabolic pathways are coupled to the circadian clock. As epigenetic control is the molecular basis of cellular plasticity, these findings have far-reaching implications for human physiology and disease.